The overall purpose of this Program Project competing renewal application is to continue to investigate the neurobiology of stress and depression, using a combination of anatomical, molecular biological endocrine, and behavioral tools, in the context of four individual projects. The main focus is to understand the limbic neuronal circuits which participate in the evaluation of stressors, and transduce the activation and termination of stress responses. A particular interest is to link this anatomical information with a more functional perspective, in an attempt to understand the neuronal basis of individual differences in stress responsiveness, as well as differences which accompany coping and social control (P1). While this level of analysis captures the system at one point in time, a main interest is to understand the plasticity of the system - i.e., how this complex circuitry is laid down during development; how differences in stress responsiveness may emerge and affect function later on in life, including old age; and how repeated or multiple stress alters the organism's response to subsequent stressors (P2). These basic studies form the foundation for studies in human postmortem brain which investigate the elements of stress circuitry in humans, its interface with systems which are likely altered by antidepressant drugs, and its alteration by the processes that result in suicide (P3). Finally, the combination of these basic and pre-clinical studies offer a rich framework in which to address some questions regarding the neuronal basis of stress and depression in humans. This latter set of studies draws on almost all the elements above to frame its central question: is the neurobiology of stress a key to understanding the biological basis of depression? (P4)